Identify at-risk populations to improve the prevention and early detection of AK.

Describe currently used therapies in the treatment of AK.

Analyze the prognosis for the different stages and the efficacy of treatment options.

Demonstrate a measurable improvement in practice, exhibited by increased early diagnosis of AK.

The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity.

ACCREDITATION STATEMENT
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education
for physicians.

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The estimated time to complete this educational activity: 1.5 hours.

Release date: October 15, 2007. Expiration date: October 15, 2009.

DISCLAIMER STATEMENT
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The Johns Hopkins University School of Medicine name implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an educational grant from Dermik Laboratories,
a business of sanofi-aventis U.S. LLC.

Full Disclosure Policy Affecting CME Activities:
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Program Director and Participating Faculty reported the following:

Roberta Sengelmann, MD
Associate Professor, Dermatology and Otolaryngology
Director, Dermatologic and Cosmetic Surgery
Washington University School of Medicine
St. Louis, Missouri
• Dr Sengelmann reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Notice: The audience is advised that articles in this CME activity contain reference(s) to unlabeled or unapproved uses of drugs or devices.

Dr Ditre—peels with 5-fluorouracil for treatment of actinic keratoses.
Dr Sengelmann—imiquimod for actinic keratoses may be mentioned.

All other faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.

Johns Hopkins Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Johns Hopkins Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

Skin cancer is the most common of human cancers, accounting for approximately 50% of all cancer cases, or more than 1 million new cases per year in the United States.1 Approximately 50% of Americans who live to the age of 65 develop at least 1 skin cancer.2 Nonmelanoma skin cancers, which include basal cell carcinoma and squamous cell carcinoma (SCC), account for more than 33% of all cancer cases in the United States.3 The incidence of SCC increased by approximately 4% to 8% per year from the 1960s through the 1980s and has continued to increase during the past 2 decades.4,5

Actinic keratosis (AK) is the earliest identifiable skin lesion that has the potential to progress to SCC.3 AKs are not clinically benign, cosmetic skin lesions: they are premalignancies that represent an early stage of SCC in situ. According to the American Academy of Dermatology (AAD), approximately 60% of Americans who are fair skinned or who have other high-risk features develop at least 1 AK lesion.6 Patient factors that are associated with a high risk of nonmelanoma skin cancer also increase the risk of AK. These risk factors include older patient age, male sex, exposure to high-intensity ultraviolet (UV) light or to UV light of lower intensity for long periods of time, exposure to carcinogenic chemicals (eg, arsenic or coal tar) or ionizing radiation, immunosuppression (including immunosuppressive regimens for organ transplantation), and rare genetic conditions of skin pigmentation.7,8

The most important cause of AK is exposure to UV-B radiation, which is thought to increase the risk of AK by at least 3 mechanisms: DNA damage of epidermal cells, mutation of tumor-suppressing genes, and immunosuppression.9,10 In general, the effects of UV exposure on DNA damage depend on the duration of exposure. Acute UV exposure causes DNA damage that is characterized by the formation of linked pyrimidine dimers within keratinocyte DNA.11 This DNA damage promotes the induction of the tumor-suppressing p53 gene, leading to cell cycle arrest and DNA repair. If the DNA damage cannot be repaired, p53 promotes apoptosis. Long-term, recurrent exposure to UV radiation causes the gradual loss of the normal structure and function of the skin. This results in symptoms of skin photoaging, such as dryness, irregular pigmentation, wrinkling, and other changes. These visible manifestations of sun exposure are accompanied by cumulative DNA damage, which results in mutation of p53 and other genes that normally help to suppress the formation of tumors. Chronic UV exposure also produces persistent suppression of immune function. Together, the accumulation of genetic mutations and the loss of immune function increase the likelihood of malignancy. The acute and chronic effects of UV exposure are summarized in Figures 1 and 2.11

Actinic keratoses are usually diagnosed clinically, on the basis of visual examination and palpation.9,12 The typical appearance of an AK lesion is red, scaling skin, with papules or plaques, located on a sun-exposed area. The lesions may also be skin-colored, brown, pink, pigmented, or hyperkeratotic, and vary in size from as small as 1 to 3 mm to as large as several centimeters in diameter. AKs are usually found on the scalp, face, or dorsal surface of the hands. Palpation of the lesion often reveals skin that is rough or gritty in comparison with normal skin. AK lesions are often sensitive to touch, may burn or sting, and tend to bleed easily. A biopsy may be needed to distinguish a hypertrophic AK from early SCC. Biopsy should be considered when the lesion recurs after treatment, has unusual features, or has features that suggest the possibility of dermal invasion, such as ulceration, large size, bleeding, or pruritus.13 AKs are defined histologically by the presence of atypical keratinocytes in the deeper portions of the epidermis. At the cellular level, changes associated with AK are identical to the changes associated with SCC or SCC in situ, and the differences between these conditions involve the extent of dermal involvement or subtle distinctions in lesion architecture.3

The increase in the number of skin cancers over the past several decades is probably due, at least in part, to increased voluntary sun exposure. The risk of AKs can be significantly reduced by several simple preventive measures, as summarized in the Table.14

It is not possible to predict with certainty whether a particular AK lesion will eventually progress to SCC. Professional societies, including the AAD, the American Cancer Society, and the Skin Cancer Foundation, therefore recommend treatment of AK lesions to prevent the progression to invasive cancer.15 In general, treatment options may be classified as either lesion-directed or field-directed.6,12 Lesion-directed therapy employs a physical treatment that focuses on 1 particular AK lesion, usually removing the lesion with a single visit. Lesion-directed methods include cryotherapy and electrodessication and curettage. Surgical excision is sometimes used to treat AK lesions and may provide diagnostic information for a lesion that is a suspected SCC. Field-directed therapies use topical medications or other treatments to target several AK lesions across a region of skin, including 5-fluorouracil (5-FU), imiquimod, and diclofenac gel. Some topical treatments, such as imiquimod and 5-FU, are also able to treat subclinical lesions. Limitations of topical therapies include the need for several weeks of treatment and the risk of bothersome adverse effects at the application site, such as redness, burning, or ulceration. Other options include photodynamic therapy, chemical peels, laser resurfacing, dermabrasion, or some combination of the various approaches.

This issue of Johns Hopkins Advanced Studies in Medicine includes case studies that describe the use of these treatment options for patients with AK in clinical practice. The first case, which describes the treatment of a single AK lesion, is presented by Roberta Sengelmann, MD, of the Washington University School of Medicine. Case 2, presented by Murad Alam, MD, of the Northwestern University Feinberg School of Medicine, discusses challenges in overcoming poor treatment response. Case 3, presented by Cherie M. Ditre, MD, of the University of Pennsylvania School of Medicine, describes the selection of treatment for a patient with a large number of confluent AKs of the face. In the final case, I provide an overview of the treatment of AK in a patient with immunosuppression following organ transplantation. In addition to the case presenters, these cases were developed with the participation of a group of experts in the diagnosis and treatment of AK, including Perry Robins, MD, of the New York University School of Medicine; Jonathon S. Weiss, MD, of Gwinnett Clinical Research Center, Snellville, Georgia; and Joseph L. Jorizzo, MD, of Wake Forest University School of Medicine, Winston-Salem, North Carolina. This monograph will provide an overview of recent research and expert opinion regarding strategies for the treatment of AK and the prevention of invasive skin cancer.